Thyromimetic antiobesity agents

ABSTRACT

The invention relates to pharmaceutical compositions and methods useful in the treatment of obesity which methods comprise administering to animal, including a human or companion animal, in need of such treatment an effective amount of a compound of the structural formula  
                 
 
     or a pharmaceutically acceptable salt, racemate or enantiomer thereof, wherein  
     R is hydroxy, esterified hydroxy or etherified hydroxy;  
     R 1  and R 2  are, independently, halogen, trifluoromethyl or lower alkyl;  
     R 3  is halogen, trifluoromethyl, lower alkyl, aryl, aryl-lower alkyl, cycloalkyl or cycloalkyl-lower alkyl, carbocyclic arylmethyl, carbocyclic aroyl, carbocyclic arylhydroxymethyl; or  
     R 3  is the radical  
                 
 
     wherein  
     R 8  is hydrogen, lower alkyl, aryl, cycloalkyl, aryl-lower alkyl or cycloalkyl-lower alkyl;  
     R 9  is hydroxy or acyloxy; R 10  is hydrogen or lower alkyl; or R 9  and R 10 , taken together with the carbon atom to which they are attached, form a carbonyl group;  
     R 4  is hydrogen, halogen, trifluoromethyl or lower alkyl;  
     R 5  and R 6  are, independently, hydrogen or lower alkyl or R 5  and R 6 , taken together with the carbon atom to which they are attached, form a carbonyl group;  
     X is O, S or —NR 7 ;  
     R 7  is hydrogen or lower alkyl;  
     W is O or S; and  
     Z is carboxyl or carboxyl derivatized as a pharmaceutically acceptable ester or amide.  
     The invention further provides for pharmaceutical compositions and methods of using the compounds of structural formula (I), or the pharmaceutically acceptable salts, racemates and enantiomers thereof, in combination with an anorectic agent, in treating obesity.

BACKGROUND OF THE INVENTION

[0001] This invention relates to pharmaceutical compositions and methodsuseful in treating obesity in animals, including mammalian subjects,particularly humans and companion animals.

[0002] Hitherto, the normal method employed in treating obesity has beenreduction of caloric intake, either by a reduced calorie diet or throughthe use of appetite suppressants (anorectic agents), or a combination ofthe two. In general, the use of anorectic agents alone is not entirelysatisfactory since they do not remain effective for the extended timeperiods that are necessary to achieve weight loss or they possessundesirable side-effects, particularly central stimulatory effects.

[0003] Alternatively, certain compounds have been disclosed that areable to induce weight loss by mechanisms other than appetitesuppression, e.g. through stimulation of the peripheral metabolic rateof adipose tissue. For example, U.S. Pat. Nos. 4,451,465, 4,772,631,4977,148 and 4,999,377 disclose compounds possessing thermogenicproperties at dosages causing few or no deleterious side-effects, suchas cardiac stimulation. The disclosures of U.S. Pat. Nos. 4,451,465,4,772,631, 4977,148 and 4,999,377 are incorporated herein by referencein their entirety. It is well-known to one of ordinary skill in the artthat selectivity of thermogenic effect is an important requirement for auseful therapeutic agent in the treatment of, for example, obesity andrelated conditions.

[0004] The present invention provides methods for treating obesity whichcomprise administering to an animal, including a human or companionanimal, in need of such treatment an obesity-treating amount of acompound of formula (I), or a pharmaceutically acceptable salt, racemateor enantiomer thereof, shown and defined hereinbelow.

[0005] The present invention further provides pharmaceuticalcompositions useful in the treatment of obesity which comprise anobesity-treating amount of a compound of formula (I), or apharmaceutically acceptable salt, racemate or enantiomer thereof and ananorectic agent.

[0006] The compounds of formula (I), the pharmaceutically acceptablesalts, racemates and enantiomers thereof, methods of preparing suchcompounds, salts, racemates and enantiomers and pharmaceuticalcompositions comprising such compounds, salts, racemates and enantiomersare disclosed in U.S. Pat. Nos. 5,401,772; 5,569,674 and 5,654,468, thedisclosures of which are incorporated herein by reference.

[0007] In U.S. Pat. Nos. 5,401,772; 5,569,674 and 5,654,468 there isdescribed a series of heteroacetic acid derivatives which are claimed tobe useful in the treatment of occlusive cardiovascular conditions inwhich, inter alia, hyperlipidemia and hyperlipoproteinemia areimplicated. Such conditions may include, for example, atherosclerosis,coronary heart disease and the like.

[0008] It has been subsequently disclosed in Stephan et al.,Atherosclerosis, 126, 53-63 (1996) that a representative compound ofthese derivatives, ethylN-[4-[3′-[(4-fluorophenyl)hydroxymethyl]-4′-hydroxyphenoxy]-3,5-dimethylphenyl]oxamate(CGS-26214), is devoid of both cardiovascular and thermogenic effects.

[0009] It has now been found that these heteroacetic acid derivatives,including CGS-26214, do, in fact, possess significant thermogenicproperties. Accordingly, CGS-26214 and the compounds related thereto areuseful in the treatment of obesity and related conditions.

SUMMARY OF THE INVENTION

[0010] This invention relates to methods for treating obesity whichcomprise administering to an animal, including a human or companionanimal in need of such treatment, an obesity-treating amount of acompound of formula (I) or a pharmaceutically acceptable salt, racemateor enantiomer thereof, as shown and described hereinbelow. Theadministration of a compound of formula (I), or a pharmaceuticallyacceptable salt, racemate or enantiomer thereof, provides a thermogeniceffect, that is thermogenesis is stimulated and, therefore,administration of the compound is of use in the treatment of obesity andconditions related thereto.

[0011] The invention is also directed to pharmaceutical compositions andmethods of using such compositions in treating obesity in an animal,including a human or companion animal, which methods compriseadministering to the animal in need of such treatment obesity-treatingamounts of a compound of formula (I), or a pharmaceutically acceptablesalt, racemate or enantiomer thereof, and an anorectic agent.

[0012] In a preferred aspect of the methods of this invention, theanorectic agent is selected from the group consisting ofphenylpropanolamine, ephedrine, pseudoephedrine, phentermine, aNeuropeptide Y (hereinafter referred to as “NPY”) antagonist, acholecystokinin-A (hereinafter referred to as “CCK-A”) agonist, amonoamine reuptake inhibitor, a sympathiomimetic agent, a serotoninergicagent, a dopamine agonist, a melanocyte-stimulating hormone receptoragonist or mimetic, a cannabinoid receptor antagonist, amelanocyte-stimulating hormone analog, a melanin concentrating hormoneantagonist, the OB protein (hereinafter referred to as “leptin”), aleptin analog, a galanin antagonist and an orexin receptor antagonist.An especially preferred monoamine reuptake inhibitor is sibutramine, apreferred serotoninergic agent is dexfenfluramine or fenfluramine and apreferred dopamine agonist is bromocriptine.

[0013] The pharmaceutical compositions useful in treating obesitypreferably comprise an amount of a compound of formula (I), or apharmaceutically acceptable salt, racemate or enantiomer thereof, ananorectic agent and a pharmaceutically acceptable carrier or diluent.

[0014] The invention also relates to a kit comprising an amount of acompound of formula (I), or a pharmaceutically acceptable salt, racemateor enantiomer thereof, and a pharmaceutically acceptable carrier ordiluent in a first unit dosage form, an amount of an anorectic agent anda pharmaceutically acceptable carrier or diluent in a second unit dosageform and a container.

DETAILED DESCRIPTION OF THE INVENTION

[0015] According to the instant invention, there are providedpharmaceutical compositions and methods useful for treating obesity inmammals, including humans and companion animals, which methods compriseadministering to a mammal in need of such treatment an obesity-treatingamount of a compound of the formula

[0016] or a pharmaceutically acceptable salt, racemate or enantiomerthereof, wherein

[0017] R is hydroxy, esterified hydroxy or etherified hydroxy;

[0018] R₁ and R₂ are, independently, halogen, trifluoromethyl or loweralkyl;

[0019] R₃ is halogen, trifluoromethyl, lower alkyl, lower alkanoyl,hydroxy-lower alkyl, aryl, aryl-lower alkyl, cycloalkyl orcycloalkyl-lower alkyl, carbocyclic arylmethyl, carbocyclic aroyl,carbocyclic arylhydroxymethyl; or

[0020] R₃ is the radical

[0021] wherein

[0022] R₈ is hydrogen, lower alkyl, aryl, cycloalkyl, aryl-lower alkylor cycloalkyl-lower alkyl;

[0023] R₉ is hydroxy or acyloxy; R₁₀ is hydrogen or lower alkyl; or R₉and R₁₀, taken together with the carbon atom to which they are attached,form a carbonyl group;

[0024] R₄ is hydrogen, halogen, trifluoromethyl or lower alkyl;

[0025] R₅ and R₆ are, independently, hydrogen or lower alkyl or R₅ andR₆, taken together with the carbon atom to which they are attached, forma carbonyl group;

[0026] X is O, S or-NR₇;

[0027] R₇ is hydrogen or lower alkyl;

[0028] W is O or S and

[0029] Z is carboxyl or carboxyl derivatized as a pharmaceuticallyacceptable ester or amide.

[0030] Generally preferred embodiments of the pharmaceuticalcompositions and methods of the instant invention relate to the use ofcompounds of formula (I) and the pharmaceutically acceptable salts,racemates and enantiomers thereof wherein R is located at the4′-position; R₁ and R₂ are located at the 3 and 5 positions; R₃ and R4are located at the 3′ and 5′-positions; X is O or —NR₇, W is O; R₄ ishydrogen and Z is carboxyl or carboxyl derivatized as a pharmaceuticallyacceptable ester.

[0031] A preferred embodiment of the compositions and methods of thisinvention relates to the use of a subgroup of compounds of formula (I)having the formula (II):

[0032] or the pharmaceutically acceptable salts, racemates orenantiomers thereof, wherein

[0033] R is hydroxy, esterified hydroxy or etherified hydroxy;

[0034] R₁ and R₂ are, independently, halogen, trifluoromethyl or(C₁-C₃)alkyl;

[0035] R₃ is lower alkyl, lower alkanoyl, hydroxy-lower alkyl,carbocyclic arylmethyl, carbocyclic aroyl or carbocyclic arylhydroxymethyl;

[0036] R₇ is hydrogen or lower alkyl and

[0037] Z represents carboxyl or carboxyl derivatized as apharmaceutically acceptable ester or amide.

[0038] A further preferred embodiment of the compositions and methods ofthis invention relates to the use of yet another subgroup of compoundsof formula (I) having the formula (III):

[0039] or the pharmaceutically acceptable salts, racemates orenantiomers thereof, wherein

[0040] R is hydroxy, esterified hydroxy or etherified hydroxy;

[0041] R₁ and R₂ are, independently, halogen, trifluoromethyl or(C₁-C₃)alkyl;

[0042] R₃ is lower alkyl, carbocyclic aroyl, carbocyclic arylmethyl orcarbocyclic aryl hydroxymethyl;

[0043] R₇ is hydrogen or lower alkyl and

[0044] Z represents carboxyl or carboxyl derivatized as apharmaceutically acceptable ester or amide.

[0045] Preferred compounds for use in the pharmaceutical compositionsand methods of this invention include those compounds of formula (III),and the pharmaceutically acceptable salts, racemates and enantiomersthereof, wherein R is hydroxy, acyloxy, lower alkanoyloxy, lower alkoxyor tetrahydropyranyloxy; R₁ and R₂ are the same and are halogen or(C₁-C₃)alkyl; R₃ is (C₁-C₃)alkyl or monocyclic carbocyclic arylmethyl;R₇ is hydrogen or (C₁-C₂)alkyl and Z is carboxyl or carboxyl derivatizedas a pharmaceutically acceptable ester or amide.

[0046] Further preferred compounds for use in the pharmaceuticalcompositions and methods of this invention include those compounds offormula (III), and the pharmaceutically acceptable salts, racemates andenantiomers thereof, wherein R is hydroxy; R₁ and R₂ are the same andare chloro or methyl; R₃ is isopropyl, benzyl or benzyl substituted byhalogen, lower alkyl, lower alkoxy or trifluoromethyl; R₇ is hydrogenand Z is carboxyl or lower alkoxycarbonyl.

[0047] Another preferred embodiment of the instant invention includescompounds of structural formula (III), or the pharmaceuticallyacceptable salts, racemates or enantiomers thereof, wherein R ishydroxy, lower alkanoyloxy, lower alkoxy or tetrahydropyranyloxy; R₁ andR₂ are, independently, halogen or (C₁-C₃)alkyl; R₃ is carbocyclic aroylor carbocyclic aryl hydroxymethyl; R₇ is hydrogen or (C₁-C₂)alkyl and Zis carboxyl or carboxyl derivatized as a pharmaceutically acceptableester or amide.

[0048] Yet another preferred grouping of compounds of formula (III),including the pharmaceutically acceptable salts, racemates andenantiomers thereof, are those wherein R is hydroxy; R₁ and R₂ are thesame and are chloro or methyl; R₃ is phenyl-hydroxymethyl,phenyl-hydroxymethyl substituted on phenyl by halogen, lower alkyl,lower alkoxy or trifluoromethyl or benzoyl or benzoyl substituted byhalogen, lower alkyl, lower alkoxy or trifluoromethyl; R₇ is hydrogenand Z is carboxyl or lower alkoxycarbonyl.

[0049] Especially preferred compounds of formula (I), including thepharmaceutically acceptable salts, racemates and enantiomers thereof,which are useful in the pharmaceutical compositions and methods of theinstant invention areN-[3,5-dimethyl-4-(4′-hydroxy-3′-isopropylphenoxy)-phenyl]-oxamic acid(CGS-23425),N-[3,5-dichloro-4-(4′-hydroxy-3′-isopropylphenoxy)-phenyl]-oxamic acid,ethylN-[4-[3′-[(4-fluorophenyl)hydroxymethyl]-4′-hydroxyphenoxy]-3,5-dimethylphenyl]oxamate(CGS-26214) andN-[4-[3′-[(4-fluorophenyl)hydroxymethyl]-4′-hydroxyphenoxy]-3,5-dimethylphenyl]oxamicacid.

[0050] Certain compounds employed in the pharmaceutical compositions andmethods of this invention may have one or more asymmetric centers andcan exist in the form of racemates, and enantiomers thereof, all ofwhich are intended to be included within the spirit and scope of theinvention.

[0051] Unless otherwise provided, the chemical nomenclature employedherein have the following meanings within the scope of the presentinvention.

[0052] Aryl represents carbocyclic or heterocyclic aryl.

[0053] Carbocyclic aryl represents optionally substituted phenyl oroptionally substituted naphthyl.

[0054] Optionally substituted phenyl represents preferably phenyl orphenyl substituted by one to three substituents, preferably lower alkyl,hydroxy, lower alkoxy, lower alkanoyloxy, halogen, cyano,trifluoromethyl, lower alkanoylamino or lower alkoxycarbonyl.

[0055] Optionally substituted naphthyl represents 1- or 2-naphthyl or 1-or 2-naphthyl preferably substituted by lower alkyl, lower alkoxy orhalogen.

[0056] Heterocyclic aryl is preferably monocyclic heterocyclic aryl suchas optionally substituted thienyl, furanyl, pyridyl, pyrrolyl or N-loweralkylpyrrolyl.

[0057] Optionally substituted furanyl represents 2- or 3-furanyl or 2-or 3-furanyl preferably substituted by lower alkyl.

[0058] Optionally substituted pyridyl represents 2-, or 3- or 4-pyridylor 2-, or 3- or 4-pyridyl preferably substituted by lower alkyl orhalogen.

[0059] Optionally substituted thienyl represents 2- or 3-thienyl or 2-or 3-thienyl preferably substituted by lower alkyl.

[0060] Aryl as employed in the term “aryl-lower” and the like ispreferably phenyl or phenyl substituted by one or two of lower alkyl,lower alkoxy, hydroxy, lower alkanoyloxy, halogen, trifluoromethyl,cyano, lower alkanoylamino or lower alkoxycarbonyl.

[0061] Aryl-lower alkyl is benzyl or phenethyl optionally substituted byone or two of lower alkyl, lower alkoxy, hydroxy, lower alkanoyloxy,halogen or trifluoromethyl.

[0062] The term “lower” as employed herein in connection with compoundsor organic radicals defines such compounds or radicals with up to andincluding seven, preferably up to and including four and, morepreferably, one or two carbon atoms, including branched orstraight-chain configurations thereof.

[0063] A lower alkyl group preferably contains from one to four carbonatoms and represents, for example, methyl, ethyl, propyl or butyl.

[0064] A lower alkoxy group preferably contains from one to four carbonatoms and is, for example, methoxy, ethoxy, propoxy, isopropoxy orbutoxy.

[0065] Cycloalkyl is a saturated cyclic hydrocarbon radical, preferablya C₅ to C₇ cycloalkyl radical which contains five to seven ring carbonsand is, preferably, cyclopentyl or cyclohexyl.

[0066] Cycloalky-lower alkyl is preferably 1- or 2-(cyclopentyl orcyclohexyl)ethyl, 1-, 2- or 3-(cyclopentyl or cyclohexyl)propyl, or 1-,2-, 3- or 4-(cyclopentyl- or cyclohexyl)butyl.

[0067] Lower alkenyloxy represents preferably allyloxy.

[0068] Di-lower alkylamino preferably contains one to four carbon atomsin each lower alkyl portion and is, for example, N,N-dimethylamino,N-methyl-N-ethyamino and N,N-diethylamino.

[0069] Lower alkoxycarbonyl preferably contains one to four carbon atomsin the alkoxy moiety and is, for example, methoxycarbonyl,ethoxycarbonyl, propoxycarbonyl and isopropoxycarbonyl.

[0070] Hydroxy-lower alkyl is preferably hydroxymethyl.

[0071] Halogen (halo) preferably represents fluoro or chloro, but mayalso be bromo or iodo.

[0072] Lower alkanoyl is preferably acetyl, propionyl, butyryl orpivaloyl.

[0073] Lower alkanoyloxy is preferably acetoxy, propionyloxy orpivaloyloxy.

[0074] Acylamino is preferably lower alkanoylamino, aroylamino oraryl-lower alkoxycarbonylamino, such as benzyloxycarbonylamino.

[0075] Lower alkanoylamino is preferably acetamido or propionamido.

[0076] Aroyl is preferably benzoyl or benzoyl substituted on the benzenering by lower alkyl, lower alkoxy, halogen or trifluoromethyl.

[0077] Acyl is preferably lower alkanoyl, carbocyclic aryl-loweralkanoyl or carbocyclic aroyl.

[0078] Carboxyl derivatized as a pharmaceutically acceptable ester isesterified carboxyl, preferably a prodrug ester convertible bysolvolysis or under physiological conditions to the free carboxylicacid, such as being preferably lower alkoxycarbonyl; (amino, acylamino,mono- or di-lower alkylamino)-lower alkoxycarbonyl; carboxy-loweralkoxycarbonyl, e.g. α-carboxy-lower alkoxycarbonyl; loweralkoxycarbonyl-lower alkoxycarbonyl, e.g. α-lower alkoxycarbonyl-loweralkoxycarbonyl; α-(di-lower alkylamino, amino, mono-lower alkylamino,morpholino, piperidino, pyrrolidino, 1-loweralkyl-piperazino)-carbonyl-lower alkoxycarbonyl; carbocyclic orheterocyclic aryl-lower alkoxycarbonyl, preferably optionally (halogen,lower alkyl or lower alkoxy)-substituted benzyloxycarbonyl, orpyridylmethoxycarbonyl; 1-(hydroxy, lower alkanoyloxy or loweralkoxy)-lower alkoxycarbonyl, e.g. pivaloyloxymethoxycarbonyl; (hydroxy,lower alkanoyloxy or lower alkoxy)-lower alkoxymethoxycarbonyl; 1-(loweralkoxycarbonyloxy)-lower alkoxycarbonyl; 5-indanyloxycarbonyl;3-phthalidoxycarbonyl and (lower alkyl, lower alkoxy orhalogen)-substituted 3-phthalidoxycarbonyl; dihydroxypropyloxycarbonylwherein hydroxy groups are free or are protected in the form of ketals,e.g. a lower alkylidene, a benzylidene or a 5- or 6-memberedcycloalkylidene derivative, preferably being(2,2-dimethyl-1,3-dioxolan4-yl)-methoxycarbonyl.

[0079] Carboxyl derivatized as a pharmaceutically acceptable prodrugester is preferably (C₁-C₄)alkoxycarbonyl, benzyloxycarbonyl, optionallysubstituted on phenyl by lower alkyl, lower alkoxy, halogen, ortrifluoromethyl, 1-(C₂-C₄-alkanoyloxy)-ethoxycarbonyl,(2,2-dimethyl-1,3-dioxolan-4-yl)-methoxycarbonyl, 5-indanyloxycarbonyl,1-(C₁-C₄-alkoxycarbonyloxy)-ethoxycarbonyl or 3-pyridylmethoxycarbonyl.

[0080] Carboxyl derivatized as a pharmaceutically acceptable amide ispreferably carbamoyl or N-substituted carbamoyl, preferably loweralkylamino, arylamino, di-lower alkylamino, morphlino, N-loweralkylpiperazino, pyrrolidino, piperidino, (amino or acylamino)-loweralkylamino or aryl-lower alkylamino]-carbonyl.

[0081] Esterified hydroxy is acyloxy, e.g. acyloxy derived from anorganic carboxylic acid, preferably lower alkanoyloxy, aroyloxy, oraryl-lower alkanoyloxy; also3,7,12-(3α,5β,7α,12α)-trihydroxy-cholan-24-oyloxy (derived from cholicacid), and the like.

[0082] Etherified hydroxy is preferably lower alkoxy, lower alkenyloxy,(C₅-C₇)-cycloalkyoxy, carbocyclic aryl-lower alkoxy,tetrahydropyranyloxy, (C₅-C₇)-cycloalkyl-lower alkoxy, and the like.

[0083] The term “animal” is meant to embrace both companion animals andhumans. In this regard, the phrase “companion animal” is meant toembrace a hosuehold pet or other domesticated animal including, but notlimited to, cattle, sheep, ferrets, swine, horses, poultry, fish,rabbits, goats, dogs, cats and the like. Particularly preferredcompanion animals are dogs and cats.

[0084] Pharmaceutically acceptable salts are either pharmaceuticallyacceptable acid addition salts for any basic compounds used in thepharmaceutical compositions and methods of this invention or saltsderived from pharmaceutically acceptable bases for any acidic compoundsused in the pharmaceutical compositions and methods of this invention.

[0085] Pharmaceutically acceptable salts of the basic compounds used inthe pharmaceutical compositions and methods of this invention are acidaddition salts, which are preferably therapeutically acceptableinorganic or organic acids, such as strong mineral acids, for example,hydrohalic, e.g. hydrochloric, hydrobromic, sulfuric or phosphoric acid;aliphatic or aromatic carboxylic or sulphonic acids, e.g. acetic,propionic, succinic, gylcollic, lactic, malic, tartaric, gluconic,citric, maleic, fumaric, pyruvic, phenylacetic, benzoic, pamoic,nicotinic, methanesulfonic, ethanesulfonic, hydroxyethanesulfonic,1,2-ethanedisulfonic, benzenesulfonic, p-toluenesulfonic ornaphthalenesulfonic acid or ascorbic acid.

[0086] Pharmaceutically acceptable salts of the acidic compounds used inthe pharmaceutical compositions and methods of this invention, e.g.those compounds having a carboxyl group, are salts formed withpharmaceutically acceptable bases, e.g. alkali metal salts (sodium,potassium salts), alkaline earth metal salts (magnesium, calcium salts),amine salts (ethanolamine, diethanolamine, triethanolamine, trimethaminosalts).

[0087] The compounds of formula (I), including the pharmaceuticallyacceptable salts, racemates and enantiomers thereof and the preferredembodiments related thereto employed in the pharmaceutical compositionsand methods of the instant invention, may be readily prepared accordingto the teachings in the aforementioned U.S. Pat. Nos. 5,401,772;5,569,674 and 5,654,468.

[0088] One aspect of the instant invention is directed to methods oftreating obesity in an animal, including a human or companion animal,which comprise administering to an animal in need of such treatment anobesity-treating amount of a compound of formula (I), or apharmaceutically acceptable salt, racemate or enantiomer thereof.

[0089] When treating obesity, generally satisfactory results areobtained when a compound of formula (i) or a pharmaceutically acceptablesalt, racemate or enantiomer thereof, is administered to an animal,including a human or companion animal, either orally, parenterally ortransdermally. Administration by the oral route is normally preferred,being more convenient and avoiding the possible pain and irritation ofinjection. However, in circumstances where the subject cannot ingest themedication or absorption following oral administration is impaired, asby disease or other abnormality, it is essential that the compound beadministered parenterally or transdermally.

[0090] By any route of administration, the dosage of the compound offormula (I), or the pharmaceutically acceptable salt, racemate orenantiomer thereof, is in the range of from about 0.005 to about 100mg/kg body weight of the subject per day, preferably about 0.3 to about50 mg/kg body weight of the subject per day and most preferably about 1to about 10 mg/kg body weight of the subject per day, preferablyadministered singly or as a divided dose.

[0091] In a preferred aspect of the methods of this invention, thecompound of formula (I) isN-[3,5-dimethyl4-(4′-hydroxy-3′-isopropylphenoxy)-phenyl]-oxamic acid(CGS-23425) or a pharmaceutically acceptable salt thereof;N-[3,5-dichloro4-(4′-hydroxy-3′-isopropylphenoxy)-phenyl]-oxamic acid ora pharmaceutically acceptable salt thereof; ethylN-[4-[3′-[(4-fluorophenyl)hydroxymethyl]4′-hydroxyphenoxy]-3,5-dimethylphenyl]oxamate(CGS-26214) or a racemate or enantiomer thereof orN-[4-[3′-[(4-fluorophenyl)hydroxymethyl]4′-hydroxyphenoxy]-3,5-dimethylphenyl]oxamicacid, or a pharmaceutically acceptable salt, racemate or enantiomerthereof.

[0092] The instant invention is also directed to methods of treatingobesity in animal which comprise administering to an animal, including ahuman or companion animal, in need of such treatment obesity-treatingamounts of a combination comprising a compound of formula (I), or apharmaceutically acceptable salt, racemate or enantiomer thereof, and ananorectic agent.

[0093] The administration of the compound of formula (I) and theanorectic agent according to this invention can be sequential in time orsimultaneous with the simultaneous method being generally preferred. Forsequential administration, the compound of formula (I) and the anorecticagent can be administered in any order. It is generally preferred thatsuch administration be oral. It is even more preferred that theadministration be oral and simultaneous. However, if the subject beingtreated is unable to swallow, or oral absorption is otherwise impairedor undesirable, parenteral or transdermal administration will beappropriate. When the compound of formula (I) and the anorectic agentare administered sequentially, the administration of each can be by thesame method or by different methods.

[0094] In a preferred aspect of the methods of this invention, theanorectic agent is selected from the group consisting ofphenylpropanolamine, ephedrine, pseudoephedrine, phentermine, aNeuropeptide Y (hereinafter referred to as “NPY”) antagonist, acholecystokinin-A (hereinafter referred to as “CCK-A”) agonist, amonoamine reuptake inhibitor, a sympathiomimetic agent, a serotoninergicagent, a dopamine agonist, a melanocyte-stimulating hormone receptoragonist or mimetic, a cannabinoid receptor antagonist, amelanocyte-stimulating hormone analog, a melanin concentrating hormoneantagonist, the OB protein (hereinafter referred to as “leptin”), aleptin analog, a galanin antagonist and an orexin receptor antagonist.Such classes of anorectic agents are, or will be, well known to one ofordinary skill in the art.

[0095] In yet another preferred aspect of the methods of this invention,the compound of formula (I) isN-[3,5-dimethyl-4-(4′-hydroxy-3′-isopropylphenoxy)-phenyl]-oxamic acid(CGS-23425) or a pharmaceutically acceptable salt thereof;N-[3,5-dichloro4-(4′-hydroxy-3′-isopropylphenoxy)-phenyl]-oxamic acid ora pharmaceutically acceptable salt thereof; ethylN-[4-[3′-[(4-fluorophenyl)hydroxymethyl]-4′-hydroxyphenoxy]-3,5-dimethylphenyl]oxamate(CGS-26214) or a racemate or enantiomer thereof orN-[4-[3′-[(4-fluorophenyl)hydroxymethyl]-4′-hydroxyphenoxy]-3,5-dimethylpheny]oxamicacid or a pharmaceutically acceptable salt, racemate or enantiomerthereof, and the anorectic agent is selected from the group consistingof a CCK-A agonist, leptin, a leptin analog and a galanin antagonist.

[0096] In an especially preferred aspect of the methods of this instantinvention, the anorectic agent is phentermine, the monoamine reuptakeinhibitor is sibutramine, the serotoninergic agent is dexfenfluramine orfenfluramine and the dopamine agonist is bromocriptine.

[0097] The preferred anorectic agent phentermine may be prepared asdescribed in U.S. Pat. No. 2,408,345, the disclosure of which isincorporated herein by reference.

[0098] The preferred monoamine reuptake inhibitor sibutramine can beprepared as described in U.S. Pat. No. 4,929,629, the disclosure ofwhich is incorporated herein by reference.

[0099] The preferred serotoninergic agents fenfluramine anddexfenfluramine can be prepared as described in U.S. Pat. No. 3,198,834,the disclosure of which is incorporated herein by reference.

[0100] The preferred dopamine agonist bromocriptine can be prepared asdescribed in U.S. Pat. Nos. 3,752,814 and 3,752,888, the disclosures ofwhich are incorporated herein by reference.

[0101] When treating obesity, generally satisfactory results areobtained when the combination of the instant invention, i.e. a compoundof structural formula (I) or a pharmaceutically acceptable salt,racemate or enantiomer thereof, together with an anorectic agent isadministered to an animal, including a human or a companion animal,either orally, parenterally or transdermally. Administration by the oralroute is normally preferred, being more convenient and avoiding thepossible pain and irritation of injection. However, in circumstanceswhere the subject cannot ingest the medication or absorption followingoral administration is impaired, as by disease or other abnormality, itis essential that the drug be administered parenterally ortransdermally.

[0102] By any route of administration, the dosage of the compound offormula (I) or the pharmaceutically acceptable salt, racemate orenantiomer thereof, is in the range of from about 0.005 to about 100mg/kg body weight of the subject per day, preferably from about 0.3 toabout 50 mg/kg body weight of the subject per day and most preferablyfrom about 1 to about 10 mg/kg body weight of the subject per day,preferably administered singly or as a divided dose.

[0103] The dosage of the anorectic agent is generally in the range offrom about 0.01 to about 50 mg/kg body weight of the subject per day,preferably from about 0.1 to about 10 mg/kg body weight of the subjectper day, administered singly or as a divided dose.

[0104] When the anorectic agent is phentermine, the dosage ofphentermine is from about 0.01 to 10 mg/kg body weight of the subjectper day, preferably from about 0.1 to about 1 mg/kg body weight of thesubject per day.

[0105] When the anorectic agents is sibutramine, the dosage range isfrom about 0.01 to about 30 mg/kg body weight of the subject per day,preferably from about 0.1 to about 1 mg/kg body weight of the subjectper day.

[0106] When the anorectic agent is dexfenfluramine or fenfluramine, thedosage range is from about 0.01 to about 30 mg/kg body weight of thesubject per day, preferably from about 0.1 to about 1 mg/kg body weightof the subject per day.

[0107] When the anorectic agent is bromocriptine, the dosage range isfrom about 0.01 to about 10 mg/kg body weight of the subject per day,preferably from about 0.1 to about 10 mg/kg body weight of the subjectper day.

[0108] It will be appreciated that, when treating an animal according tothe methods of the instant invention, the actual preferred route ofadministration and optimum dosage utilized will be at the soundprofessional discretion of the person responsible for the treatment andmay vary according to the severity of the condition to be treated, theintended route of administration and patient characteristics such asage, weight, rate of excretion, concurrently administered medicationsand general physical condition of the subject. Normally, the optimumdosage for the subject being treated will be determined by generallyadministering smaller doses initially and thereafter incrementallymodifying the regimen, if required, to determine the most suitabledosage. This may vary according to the particular compound employed andwith the nature of the subject being treated.

[0109] The compounds of formula (I), the pharmaceutically acceptablesalts, racemates and enantiomers thereof, and combinations thereof withanorectic agents, are preferably administered in the form of apharmaceutical composition comprising a pharmaceutically acceptablecarrier or diluent. Accordingly, the compounds of formula (I), thepharmaceutically acceptable salts, racemates and enantiomers thereof,and combinations thereof with anorectic agents, can be administeredindividually or together in any conventional oral, parenteral ortransdermal dosage form.

[0110] Suitable pharmaceutically-acceptable carriers include inert solidfillers or diluents and sterile aqueous or organic solutions. The activecompounds will be present in such pharmaceutical compositions in amountssufficient to provide the desired dosage amount in the range describedabove. Thus, for oral administration, the compounds can be combined witha suitable solid or liquid carrier or diluent to form capsules, tablets,powders, syrups, solutions, suspensions and the like. The pharmaceuticalcompositions may, if desired, contain additional components such asflavorants, sweeteners, excipients and the like.

[0111] The tablets, pills, capsules, and the like may also contain abinder such as gum tragacanth, acacia, corn starch or gelatin;excipients such as dicalcium phosphate; a disintegrating agent such ascorn starch, potato starch, alginic acid; a lubricant such as magnesiumstearate; and a sweetening agent such as sucrose, lactose or saccharin.When a dosage unit form is a capsule, it may contain, in addition tomaterials of the above type, a liquid carrier such as a fatty oil.

[0112] Various other materials may be present as coatings or to modifythe physical form of the dosage unit. For instance, tablets may becoated with shellac, sugar or both. A syrup or elixir may contain, inaddition to the active ingredient, sucrose as a sweetening agent, methyland propylparabens as preservatives, a dye and a flavoring such ascherry or orange flavor.

[0113] These pharmaceutical compositions may also be administeredparenterally. For parenteral administration the pharmaceuticalcompositions can be combined with sterile aqueous or organic media toform injectable solutions or suspensions. Solutions or suspensions ofthese pharmaceutical compositions can be prepared in water suitablymixed with a surfactant such as hydroxypropylcellulose. Dispersions canalso be prepared in sesame or peanut oil, ethanol, water, polyol (e.g.,glycerol, propylene glycol and liquid polyethylene glycol), suitablemixtures thereof, vegetable oils, N-methyl glucamine,polyvinylpyrrolidone and mixtures thereof in oils as well as aqueoussolutions of water-soluble pharmaceutically acceptable salts of thecompounds. Under ordinary conditions of storage and use, thesepreparations contain a preservative to prevent the growth ofmicroorganisms. The injectable solutions prepared in this manner canthen be administered intravenously, intraperitoneally, subcutaneously,or intramuscularly, with intramuscular administration being thepreferred parenteral route in humans.

[0114] The pharmaceutical forms suitable for injectable use includesterile aqueous solutions or dispersions and sterile powders for thepreparation of sterile injectable solutions or dispersions. In allcases, the form must be sterile and must be fluid to the extent thateasy syringability exists. It must be stable under the conditions ofmanufacture and storage and must be preserved against the contaminatingaction of microorganisms such as bacteria and fungi.

[0115] The pharmaceutical compositions may also be administeredtransdermally. Suitable formulations for transdermal application includean obesity-treating amount of a compound or pharmaceutical compositionof the invention with a suitable transdermal carrier. Preferredtransdermal carriers include absorbable pharmacologically acceptablesolvents to promote and assist passge through the skin of the subjectbeing treated. Characteristically, transdermal devices comprise the formof a bandage having a backing member, a reservoir containing thecompound, optionally with carriers, optionally a rate-controllingbarrier to deliver the compound to the skin of the subject being treatedat a controlled and predetermined rate over a prolonged period of timeand means to secure the device to the skin of the subject being treated.

[0116] Methods of preparing the various pharmaceutical compositions witha desired amount of an active ingredient or ingredients are known, orwill be apparent in light of this disclosure, to one of ordinary skillin the art. See, for example, Remington's Pharmaceutical Sciences, MackPublishing Company, Easton, Pa., 15th Edition (1975).

[0117] As a consequence of their thermogenic actions, the methods andpharmaceutical compositions of the instant invention also have utilityin the treatment of obesity in companion animals, preferably dogs andcats. The administration of the pharmaceutical compositions of thisinvention may be effected orally, parenterally or transdermally. Anamount of a pharmaceutical composition of the invention is administeredsuch that an effective dose is received, normally a daily dose, as setforth hereinabove.

[0118] Conveniently, the medicaments can be carried in the drinkingwater such that a therapeutic dosage of the agents is ingested with thedaily water supply. The agents can be directly metered into drinkingwater, preferably in the form of a liquid, water-soluble concentrate,such as an aqeuous solution of a water-soluble salt.

[0119] For purposes of alternative convenience, the active ingredientscan also be added directly to the companion animal's feed, as such, orin the form of an animal feed supplement, also referred to as a premixor concentrate. A premix or concentrate of the therapeutic agent in acarrier is more commonly employed for the inclusion of the agent in thefeed. Suitable carriers are liquid or solid, as desired, such as water,various meals such as alfalfa meal, soybean meal, cottonseed oil meal,linseed oil meal, corncob meal and corn meal, molasses, urea, bone meal,and various mineral mixes. A particularly effective carrier is therespective animal feed itself, i.e., a small portion of such feed. Thecarrier facilitates uniform distribution of the active materials in thefinished feed with which the premix is blended. It is important that thecompounds be thoroughly blended into the premix and, subsequently, thefeed. In this respect, the agents may be dispersed or dissolved in asuitable oily vehicle such as soybean oil, corn oil, cottonseed oil, andthe like, or in a volatile organic solvent and then blended with thecarrier. It will be appreciated that the proportions of active materialsin the concentrate are capable of wide variation since the amount ofagent in the finished feed may be adjusted by blending the appropriateproportion of premix with the feed to obtain a desired level of thetherapeutic agents.

[0120] High potency concentrates may be blended by the feed manufacturerwith a proteinaceous carrier such as soybean oil meal and other meals,as described above, to produce concentrated supplements which aresuitable for direct feeding to animals. In such instances, the animalsare permitted to consume the usual diet. Alternatively, suchconcentrated supplements may be added directly to the feed to produce anutritionally balanced, finished feed containing a therapeuticallyeffective level of a compound according to this invention. The mixturesare thoroughly blended by standard procedures, such as in a twin shellblender, to insure homogeniety. If the supplement is used as a topdressing for the feed, it likewise helps to insure uniformity ofdistribution of the active ingredient across the top of the dressedfeed.

[0121] For veterinary uses, both paste and pellet formulations may alsobe conveniently employed. Paste formulations can be prepared readily bydispersing the active compounds in a pharmaceutically acceptable oilsuch as peanut oil, sesame oil, corn oil, and the like. Similarly,pellets containing an effective amount of the compounds of the instantinvention can be prepared by admixing the compounds of this inventionwith a suitable diluent such as carbowax, carnuba wax, and the like, anda lubricant, such as magnesium or calcium stearate, can be employed toimprove the pelleting process.

[0122] Since the instant invention relates to the treatment of obesitywith a combination of active ingredients which may be administeredseparately, the invention also relates to combining separatepharmaceutical compositions in kit form. A kit, according to thisinvention, comprises two separate pharmaceutical compositions: a firstunit dosage form comprising a compound of formula (I), or apharmaceutically acceptable salt, racemate or enantiomer thereof, and apharmaceutically acceptable carrier or diluent and a second unit dosageform comprising an anorectic agent and a pharmaceutically acceptablecarrier or diluent. The kit further comprises a container. The containeris used to contain the separate pharmaceutical compositions and maycomprise, for example, a divided bottle or a divided foil packet,however, the separate pharmaceutical compositions may also be containedwithin a single, undivided container. Normally, the kit will alsoinclude directions for the administration of the separate components.The kit form is particularly advantageous when the separate componentsare preferably administered in different dosage forms (e.g., oral andparenteral), are administered at different dosage levels, or whentitration of the individual components of the combination is desired bythe prescribing physician.

[0123] One example of such a kit comprises a so-called blister pack.Blister packs are well known in the packaging industry and are beingused widely for the packaging of pharmaceutical unit dosage forms(tablets, capsules and the like). Blister packs generally comprise asheet of relatively rigid material covered with a foil of a preferablytransparent plastic material. During the packaging process recesses areformed in the plastic foil. The recesses generally conform to the sizeand shape of the tablets or capsules to be contained therein. Next, thetablets or capsules are placed in the recesses and the sheet ofrelatively rigid material is sealed against the plastic foil at the faceof the foil which is opposite from the direction in which the recesseswere formed. As a result, the tablets or capsules are sealed in therecesses between the plastic foil and the sheet. Preferably, thestrength of the sheet is such that the tablets or capsules may beremoved from the blister pack by the application of manual pressure onthe recesses whereby an opening is formed in the sheet at the place ofthe recess. The tablet or capsule can then be removed through the formedopening.

[0124] It is further desirable to provide a memory aid on the pack,e.g., in the form of numbers or similar indicia next to the tablets orcapsules whereby the indicia correspond with the days of the regimenwhich the dosage form so specified is to be ingested. An additionalexample of such a memory aid is a calendar printed on the pack, e.g., asfollows “First Week, Monday, Tuesday, . . . etc. . . . Second Week,Monday, Tuesday, . . .” etc. Other variations will be readily apparent.A “daily dose” can be a single tablet or capsule or multiple tablets orcapsules to be ingested on a given day. Also, a daily dose comprising acompound of formula (I), or a pharmaceutically acceptable salt, racemateor enantiomer thereof, can consist of one tablet or capsule while adaily dose comprising an anorectic agent can consist of multiple tabletsor capsules, or vice versa. The memory aid should reflect this.

[0125] In another specific embodiment of the invention, a pack designedto dispense the daily doses one at a time in the order of their intendeduse is provided. Preferably, the pack is equipped with a memory aid, soas to further facilitate compliance with the dosage regimen. An exampleof such a memory aid is a mechanical counter which indicates the numberof daily doses to be dispensed. Another example of such a memory aid isa battery-powered micro-chip memory coupled with a liquid crystalreadout, or audible reminder signal which, for example, reads out thedate that the last daily dose has been taken and/or reminds the patientwhen the next dose is to be taken.

EXPERIMENTAL

[0126] The consumption of oxygen by animals to produce heat is aprinciple well known to one of ordinary skill in the art. See, forexample, M. Kleiber, “The Fire of Life”, Robert E. Kreiger Pub. Co., NewYork, N.Y., 1975.

[0127] During increased energy expenditure, metabolic fuels, e.g.glucose or fatty acids, are oxidized to CO₂ and H₂O with concomitantevolution of heat, i.e. thermogenesis. Thus, the measurement of oxygenconsumption in animals, including humans and companion animals, is anindirect measure of thermogenetic effect. In this regard, indirectcalorimetry has been demonstrated to be a valid method for themeasurement of energy expenditure and has been employed extensively inanimals, including humans.

[0128] The ability of the compounds of formula (I), theirpharmaceutically acceptable salts, racemates and enantiomers thereof, togenerate a thermogenic response and, therefore, to have utility in thetreatment of obesity is demonstrated in the following protocol.

[0129] This in vivo screen is designed to evaluate the efficacy andcardiac effects of compounds that are tissue selective thyroid hormoneagonists. The efficacy endpoints measured are whole body oxygenconsumption and the activity of liver mitochrondrialalpha-glycerophosphate dehydrogenase (mGPDH). The cardiac endpoints thatare measured are heart weight and heart mGPDH activity. The protocolinvolves dosing fatty Zucker rats for 6 days, then measuring oxygenconsumption and harvesting of tissues for preparation of mitochondriaand assaying of enzyme activity.

[0130] Male fatty Zucker rats having a body weight range of about400-500 g are housed at least 3-7 d in individual cages under standardlaboratory conditions prior to the initiation of the study.

[0131] A compound of formula (I) or a pharmaceutically acceptable salt,racemate or enantiomer thereof, vehicle or 3,3′5-triiodo-L-thyroninesodium salt (T3) is administered by oral gavage as a single daily dosegiven between 3 and 6 p.m. for 6 days. The compound of formula (I), or apharmaceutically acceptable salt, racemate or enantiomer thereof, or T3is dissolved in a small volume of 1 NaOH and then brought up to theappropriate volume with 0.01 N NaOH containing 0.25% methyl cellulose(the ratio of 0.01 N NaOH/MC to 1 N NaOH is 10:1). The dosing volume is1 ml.

[0132] Oxygen consumption is measured the day after the last dose ofcompound is given using an open circuit, indirect calorimeter (Oxymax,Columbus Instruments, 950 North Hague Ave., Columbus, Ohio 43204). TheOxymax gas sensors are calibrated with N₂ gas and gas mixture (0.5% CO₂,20.5% O₂, 79% N₂) before each experiment. Rats are removed from theirhome cages, their body weights are recorded and they are placed insealed chambers (43×43×10 cm) of the calorimeter and the chambers areplaced in activity monitors. Air flow rate through the chambers is setat 1.6-1.7 l/min. The Oxymax calorimeter software calculates the oxygenconsumption (ml/kg/h) based on the flow rate of air through the chambersand difference in oxygen content at inlet and output ports. The activitymonitors have 15 infrared light beams spaced one inch apart on eachaxis; ambulatory activity is recorded when two consecutive beams arebroken and the results are recorded as counts. Oxygen consumption andambulatory activity are measured every 10 minutes for 5-6.5 hours.Resting oxygen consumption is calculated on individual rats by averagingthe values excluding the first 5 values and values obtained during timeperiods where ambulatory activity exceeds 100 counts.

[0133] When evaluated in the experimental protocol described hereinaboveutilizing fatty Zucker rats, the compound ethylN-[4-[3′-[(4-fluorophenyl)hydroxymethyl]4′-hydroxyphenoxy]-3,5-dimethylphenyl]oxamate(CGS-26214) stimulated oxygen consumption by 14 to 31% at doses of 0.005to 0.3 mg/kg body weight and the compoundN-[3,5-dimethyl4-(4′-hydroxy-3′-isopropylphenoxy)-phenyl]-oxamic acid(CGS-23425) stimulated oxygen consumption by 27% at a dose of 1.0 mg/kgbody weight.

1. A method of treating obesity in an animal which comprisesadministering to an animal in need of such treatment an obesity-treatingamount of a compound of the formula

or a pharmaceutically acceptable salt, racemate or enantiomer thereof,wherein R is hydroxy, esterified hydroxy or etherified hydroxy; R₁ andR₂ are, independently, halogen, trifluoromethyl or lower alkyl; R₃ ishalogen, trifluoromethyl, lower alkyl, lower alkanoyl, aryl,hydroxy-lower alkyl, aryl-lower alkyl, cycloalkyl or cycloalkyl-loweralkyl, carbocyclic arylmethyl, carbocyclic aroyl, carbocyclicarylhydroxymethyl; or R₃ is the radical

wherein R₈ is hydrogen, lower alkyl, aryl, cycloalkyl, aryl-lower alkylor cycloalkyl-lower alkyl; R₉ is hydroxy or acyloxy; R₁₀ is hydrogen orlower alkyl; or R₉ and R₁₀, taken together with the carbon atom to whichthey are attached, form a carbonyl group; R₄ is hydrogen, halogen,trifluoromethyl or lower alkyl; R₅ and R₆ are, independently, hydrogenor lower alkyl or R₅ and R₆, taken together with the carbon atom towhich they are attached, form a carbonyl group; X is O, S or —NR₇; R₇ ishydrogen or lower alkyl; W is O or S; and Z is carboxyl or carboxylderivatized as a pharmaceutically acceptable ester or amide.
 2. A methodaccording to claim 1 which comprises administering a compound of formula(I) or a pharmaceutically acceptable salt, racemate or enantiomerthereof, wherein R is located at the 4′-position, R₁ and R₂ are locatedat the 3 and 5 positions and R₃ and R₄ are located at the 3′ and5′-positions.
 3. A method according to claim 1 which comprisesadministering a compound of formula (I), or a pharmaceuticallyacceptable salt, racemate or enantiomer thereof, wherein X is O or —NR₇;W is O; R₄ is hydrogen and Z is carboxyl or carboxyl derivatized as apharmaceutically acceptable ester.
 4. A method according to claim 1which comprises administering a compound of the formula

or a pharmaceutically acceptable salt, racemate or enantiomer thereofwherein, R is hydroxy, esterified hydroxy or etherified hydroxy; R₁ andR₂ are, independently, halogen, trifluoromethyl or (C₁-C₃)alkyl; R₃ islower alkyl, lower alkanoyl, hydroxy-lower alkyl, carbocyclicarylmethyl, carbocyclic aroyl or carbocyclic aryl hydroxymethyl; R₇ ishydrogen or lower alkyl; and Z is carboxyl or carboxyl derivatized as apharmaceutically acceptable ester or amide.
 5. A method according toclaim 1 which comprises administering a compound of the formula

or a pharmaceutically acceptable salt, racemate or enantiomer thereof,wherein R is hydroxy, esterified hydroxy or etherified hydroxy; R₁ andR₂ are, independently, halogen, trifluoromethyl or (C₁-C₃)alkyl; R₃ islower alkyl, carbocyclic aroyl, carbocyclic arylmethyl or carbocyclicaryl hydroxymethyl; R₇ is hydrogen or lower alkyl; and Z is carboxyl orcarboxyl derivatized as a pharmaceutically acceptable ester or amide. 6.A method according to claim 5 which comprises administering a compoundof formula (III), or a pharmaceutically acceptable salt, racemate orenantiomer thereof, wherein R is hydroxy, acyloxy, lower alkoxy ortetrahydropyranyloxy.
 7. A method according to claim 5 which comprisesadministering a compound of formula (III), or a pharmaceuticallyacceptable salt, racemate or enantiomer thereof, wherein R is hydroxy,lower alkanoyloxy, lower alkoxy or tetrahydropyranyloxy; R₁ and R₂ arethe same and are halogen or (C₁-C₃)alkyl; R₃ is (C₁-C₃)alkyl ormonocyclic carbocyclic arylmethyl; R₇ is hydrogen or (C₁-C₂)alkyl and Zis carboxyl or carboxyl derivatized as a pharmaceutically acceptableester or amide.
 8. A method according to claim 5 which comprisesadministering a compound of formula (III), or a pharmaceuticallyacceptable salt, racemate or enantiomer thereof, wherein Z is carboxylor carboxyl derivatized as a pharmaceutically acceptable ester.
 9. Amethod according claim 5 which comprises administering a compound offormula (III), or a pharmaceutically acceptable salt, racemate orenantiomer thereof, wherein R is hydroxy, R₁ and R₂ are the same and arechloro or methyl; R₃ is isopropyl, benzyl or benzyl substituted byhalogen, lower alkyl, lower alkoxy or trifluoromethyl; R₇ is hydrogenand Z is carboxyl or lower alkoxycarbonyl.
 10. A method according toclaim 9 which comprises administeringN-[3,5-dimethyl-4-(4′-hydroxy-3′-isopropylphenoxy)-phenyl]-oxamic acidor a pharmaceutically acceptable salt thereof.
 11. A method according toclaim 9 which comprises administeringN-[3,5-dichloro-4-(4′-hydroxy-3′-isopropylphenoxy)-phenyl]-oxamic acidor a pharmaceutically acceptable salt thereof.
 12. A method according toclaim 5 which comprises administering a compound of formula (III), or apharmaceutically acceptable salt, racemate or enantiomer thereof,wherein R is hydroxy, lower alkanoyloxy, lower alkoxy ortetrahydropyranyloxy; R₁ and R₂ are, independently, halogen or(C₁-C₃)alkyl; R₃ is carbocyclic aroyl or carbocyclic aryl hydroxymethyl;R₇ is hydrogen or (C₁-C₂)alkyl and Z is carboxyl or carboxyl derivatizedas a pharmaceutically acceptable ester or amide.
 13. A method accordingto claim 12 which comprises administering a compound of formula (III),or a pharmaceutically acceptable salt, racemate or enantiomer thereof,wherein R is hydroxy; R₁ and R₂ are the same and are chloro or methyl;R₃ is phenyl-hydroxymethyl or phenyl-hydroxymethyl substituted on phenylby halogen, lower alkyl, lower alkoxy or trifluoromethyl, or benzoyl orbenzoyl substituted by halogen, lower alkyl, lower alkoxy ortrifluoromethyl; R₇ is hydrogen and Z is carboxyl or loweralkoxycarbonyl.
 14. A method according to claim 13 which comprisesadministering ethylN-[4-[3′-[(4-fluorophenyl)hydroxymethyl]4′-hydroxyphenoxy]-3,5-dimethylphenyl]oxamateor a racemate or enantiomer thereof.
 15. A method according to claim 13which comprises administeringN-[4-[3′-[(4-fluorophenyl)hydroxymethyl]-4′-hydroxyphenoxy]-3,5-dimethylphenyl]oxamicacid, or a pharmaceutically acceptable salt, racemate or enantiomerthereof.
 16. A method of treating obesity in an animal which comprisesadministering to an animal in need of such treatment obesity-treatingamounts of a compound of the formula

or a pharmaceutically acceptable salt, racemate or enantiomer thereof,wherein R is hydroxy, esterified hydroxy or etherified hydroxy; R₁ andR₂ are, independently, halogen, trifluoromethyl or lower alkyl; R₃ ishalogen, trifluoromethyl, lower alkyl, aryl, aryl-lower alkyl,cycloalkyl or cycloalkyl-lower alkyl, carbocyclic arylmethyl,carbocyclic aroyl, carbocyclic arylhydroxymethyl; or R₃ is the radical

wherein R₈ is hydrogen, lower alkyl, aryl, cycloalkyl, aryl-lower alkylor cycloalkyl-lower alkyl; R₉ is hydroxy or acyloxy; R₁₀ is hydrogen orlower alkyl; or R₉ and R₁₀, taken together with the carbon atom to whichthey are attached, form a carbonyl group; R₄ is hydrogen, halogen,trifluoromethyl or lower alkyl; R₅ and R₆ are, independently, hydrogenor lower alkyl or R₅ and R₆, taken together with the carbon atom towhich they are attached, form a carbonyl group; X is O, S or-NR₇; R₇ ishydrogen or lower alkyl; W is O or S; and Z is carboxyl or carboxylderivatized as a pharmaceutically acceptable ester or amide and ananorectic agent.
 17. A method according to claim 16 which comprisesadministeringN-[3,5-dimethyl4-(4′-hydroxy-3′-isopropylphenoxy)-phenyl]-oxamic acid ora pharmaceutically acceptable salt thereof.
 18. A method according toclaim 16 which comprises administeringN-[3,5-dichloro4-(4′-hydroxy-3′-isopropylphenoxy)-phenyl]-oxamic acid ora pharmaceutically acceptable salt thereof.
 19. A method according toclaim 16 which comprises administering ethylN-[4-[3′-[(4-fluorophenyl)hydroxymethyl]-4′-hydroxyphenoxy]-3,5-dimethylphenyl]oxamateor a racemate or an enantiomer thereof.
 20. A method according to claim16 which comprises administeringN-[4-[3′-[(4-fluorophenyl)hydroxymethyl]-4′-hydroxyphenoxy]-3,5-dimethylphenyl]oxamicacid or a pharmaceutically acceptable salt, racemate or enantiomerthereof.
 21. A method according to claim 16 wherein said anorectic agentis selected from the group consisting of phenylpropanolamine, ephedrine,pseudoephedrine, phentermine, an NPY antagonist, a CCK-A agonist, amonoamine reuptake inhibitor, a sympathiomimetic agent, a serotoninergicagent, a dopamine agonist, a melanocyte-stimulating hormone receptoragonist or mimetic, a cannabinoid receptor antagonist, amelanocyte-stimulating hormone analog, a melanin concentrating hormoneantagonist, leptin, a leptin analog, a galanin antagonist and an orexinreceptor antagonist.
 22. A method according to claim 21 wherein saidanorectic agent is a CCK-A agonist.
 23. A method according to claim 21wherein said anorectic agent is leptin or a leptin analog.
 24. A methodaccording to claim 21 wherein said anorectic agent is a galaninantagonist.
 25. A method according to claim 21 wherein said anorecticagent is phentermine.
 26. A method according to claim 21 wherein saidmonoamine reuptake inhibitor is sibutramine.
 27. A method according toclaim 21 wherein said serotoninergic agent is dexfenfluramine orfenfluramine.
 28. A pharmaceutical composition which comprises amountsof a compound of the formula

or a pharmaceutically acceptable salt, racemate or enantiomer thereof,wherein R is hydroxy, esterified hydroxy or etherified hydroxy; R₁ andR₂ are, independently, halogen, trifluoromethyl or lower alkyl; R₃ ishalogen, trifluoromethyl, lower alkyl, aryl, aryl-lower alkyl,cycloalkyl or cycloalkyl-lower alkyl, carbocyclic arylmethyl,carbocyclic aroyl, carbocyclic arylhydroxymethyl; or R₃ is the radical

wherein R₈ is hydrogen, lower alkyl, aryl, cycloalkyl, aryl-lower alkylor cycloalkyl-lower alkyl; R₉ is hydroxy or acyloxy; R₁₀ is hydrogen orlower alkyl; or R₉ and R₁₀, taken together with the carbon atom to whichthey are attached, form a carbonyl group; R₄ is hydrogen, halogen,trifluoromethyl or lower alkyl; R₅ and R₆ are, independently, hydrogenor lower alkyl or R₅ and R₆, taken together with the carbon atom towhich they are attached, form a carbonyl group; X is O, S or —NR₇; R₇ ishydrogen or lower alkyl; W is O or S; and Z is carboxyl or carboxylderivatized as a pharmaceutically acceptable ester or amide and ananorectic agent.
 29. A pharmaceutical composition of claim 28 whichfurther comprises a pharmaceutically acceptable carrier or diluent. 30.A method of treating obesity in an animal in need of such treatmentwhich method comprises administering to said animal an obesity-treatingamount of a composition of claim
 28. 31. A method according to claim 30wherein said compound of formula (I) isN-[3,5-dimethyl4-(4′-hydroxy-3′-isopropylphenoxy)-phenyl]-oxamic acid ora pharmaceutically acceptable salt thereof.
 32. A method according toclaim 30 wherein said compound of formula (I) isN-[3,5-dichloro-4-(4′-hydroxy-3′-isopropylphenoxy)-phenyl]-oxamic acidor a pharmaceutically acceptable salt thereof.
 33. A method according toclaim 30 wherein said compound of formula (I) is ethylN-[4-[3′-[(4-fluorophenyl)hydroxymethyl]4′-hydroxyphenoxy]-3,5-dimethylphenyl]oxamateor a racemate or an enantiomer thereof.
 34. A method according to claim30 wherein said compound of formula (I) isN-[4-[3′-[(4-fluorophenyl)hydroxymethyl]-4′-hydroxyphenoxy]-3,5-dimethylphenyl]oxamicacid or a pharmaceutically acceptable salt, racemate or enantiomerthereof.
 35. A method according to claim 30 wherein said anorectic agentis selected from the group consisting of phenylpropanolamine, ephedrine,pseudoephedrine, phentermine, an NPY antagonist, a CCK-A agonist, amonoamine reuptake inhibitor, a sympathiomimetic agent, a serotoninergicagent, a dopamine agonist, a melanocyte-stimulating hormone receptoragonist or mimetic, a cannabinoid receptor antagonist, amelanocyte-stimulating hormone analog, a melanin concentrating hormoneantagonist, leptin, a leptin analog, a galanin antagonist and an orexinreceptor antagonist.
 36. A method according to claim 35 wherein saidanorectic agent is a CCK-A agonist.
 37. A method according to claim 35wherein said anorectic agent is leptin or a leptin analog.
 38. A methodaccording to claim 35 wherein said anorectic agent is a galaninantagonist.
 39. A method according to claim 35 wherein said anorecticagent is phentermine.
 40. A method according to claim 35 wherein saidmonoamine reuptake inhibitor is sibutramine.
 41. A method according toclaim 35 wherein said serotoninergic agent is dexfenfluramine orfenfluramine.
 42. A method according to claim 35 wherein said dopamineagonist is bromocriptine.
 43. A kit which comprises an amount of acompound of the formula

or a pharmaceutically acceptable salt, racemate or enantiomer thereof,wherein R is hydroxy, esterified hydroxy or etherified hydroxy; R₁ andR₂ are, independently, halogen, trifluoromethyl or lower alkyl; R₃ ishalogen, trifluoromethyl, lower alkyl, aryl, aryl-lower alkyl,cycloalkyl or cycloalkyl-lower alkyl, carbocyclic arylmethyl,carbocyclic aroyl, carbocyclic arylhydroxymethyl; or R₃ is the radical

wherein R₈ is hydrogen, lower alkyl, aryl, cycloalkyl, aryl-lower alkylor cycloalkyl-lower alkyl; R₉ is hydroxy or acyloxy; R₁₀ is hydrogen orlower alkyl; or R₉ and R₁₀, taken together with the carbon atom to whichthey are attached, form a carbonyl group; R₄ is hydrogen, halogen,trifluoromethyl or lower alkyl; R₅ and R₆ are, independently, hydrogenor lower alkyl or R₅ and R₆, taken together with the carbon atom towhich they are attached, form a carbonyl group; X is O, S or —NR₇; R₇ ishydrogen or lower alkyl; W is O or S; and Z is carboxyl or carboxylderivatized as a pharmaceutically acceptable ester or amide and apharmaceutically acceptable carrier or diluent in a first unit dosageform, an amount of an anorectic agent and a pharmaceutically acceptablecarrier or diluent in a second unit dosage form and a container.